Flow-Dependent Dilation Mediated by Endogenous Kinins Requires Angiotensin AT ₂ Receptors

Abstract

Abstract-The vascular kallikrein-kinin system contributes to about one third of flow-dependent dilation in mice carotid arteries, by activating bradykinin B 2 receptors coupled to endothelial nitric oxide (NO) release. Because the bradykinin/NO pathway may mediate some of the effects of angiotensin II AT 2 receptors, we examined the possible contribution of AT 2 receptors to the kinin-dependent response to flow. Changes in outer diameter after increases in flow rate were evaluated in perfused arteries from wild-type animals (TK ϩ/ϩ ) and in tissue kallikrein-deficient mice (TK Ϫ/Ϫ ) in which the presence of AT 2 receptor expression was verified. Saralasin, a nonselective angiotensin II receptor antagonist, impaired significantly flow-induced dilation in TK ϩ/ϩ , whereas it had no effect in TK Ϫ/Ϫ mice. In both groups, blockade of AT 1 receptors with losartan or candesartan did not affect the response to flow. Inhibition of AT 2 receptors with PD123319 reduced significantly flow-induced dilation in TK ϩ/ϩ mice, but had no significant effect in TK Ϫ/Ϫ mice. Combining PD123319 with the bradykinin B 2 receptor antagonist HOE-140 had no additional effect to AT 2 receptor blockade alone in TK ϩ/ϩ arteries. Flow-dependent-dilation was also impaired in AT 2 receptor deficient mice (AT 2 Ϫ/Ϫ ) when compared with wild-type littermates. Furthermore, HOE-140 significantly reduced the response to flow in the AT 2 ϩ/ϩ , but not in AT 2 Ϫ/Ϫ mice. In conclusion, this study demonstrates that the presence of functional AT 2 receptors is necessary to observe the contribution of the vascular kinin-kallikrein system to flow-dependent dilation.

Evidence for a Functional Interaction of the Angiotensin-(1–7) Receptor Mas With AT 1 and AT 2 Receptors in the Mouse Heart

“…15,39 In addition, in Mas-deficient mice, the specific binding of Ang-(1-7) to kidney slices was abolished, whereas the binding of Ang II to AT 2 receptors was fully preserved. 15 Thus, a functional interaction such as a cross-talk mechanism or a permissive role for the AT 2 receptor for some Masmediated effects, as recently suggested for B 2 receptormediated bradykinin effects, 45 should be considered. It should be pointed out that, despite its putative interaction with the Ang-(1-7) receptor Mas, the role of AT 2 receptors within the RAS is still unclear.…”

Direct evidence for the role of caveolin-1 and caveolae in mechanotransduction and remodeling of blood vessels

“…Since in vitro flow-dependent dilation is known to be partially NO dependent (22)(23)(24) and Cav-1 is considered a negative regulator of eNOS function (2,3,25), we examined responses to another endothelium-dependent vasodilator, acetylcholine (Ach), in pressurized carotid arteries. In carotid arteries isolated from eNOS knockout mice, Ach-mediated vasodilation is absent, demonstrating that eNOS-derived NO is the major endothelial-derived relaxant in these vessels (26).…”

Response to Angiotensin-(1-7) and Bradykinin in Baroreceptor Reflex Sensitivity in Hypertension

“…It is well established that there are interactions between bradykinin and Ang-(1-7), as well as other components of the RAS that may reflect an interaction through the common metabolism pathway involving angiotensin-converting enzyme, release of bradykinin by Ang-(1-7), or potential receptor interactions. [2][3][4][5] In an earlier study, however, we demonstrated that the effects of a peptidic angiotensin-converting enzyme inhibitor injected acutely into the nucleus of the solitary tract were mediated primarily by Ang-(1-7) but not by bradykinin. 6 Specifically, the selective Ang-(1-7) antagonist d-Ala 7 -Ang-(1-7) (A779) blocked the improvement in the baroreflex, but the bradykinin antagonist HOE 140 had no effect in that study.…”